In general, as disorders for which immunosuppressive agents may be used, mention may be made of a number of autoimmune diseases such as rejection after transplantation of organs or tissues, graft versus host disease after bone-marrow transplantation, inflammatory bowel diseases such as ulcerative colitis or Crohn disease, inflammatory or allergenic skin diseases such as psoriasis or atopic dermatitis, inflammatory or allergenic respiratory disorders such as chronic obstructive pulmonary disease or asthma, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Sjögren syndrome, or the like. In addition, immunosuppressive agents such as cyclophosphamide or methotrexate are employed also in the treatment of hematologic neoplasms such as multiple myeloma, malignant lymphoma, leukemia or the like. Furthermore, immunosuppressive agents may also be employed in combination with antibiotics in the case of the treatment of disorders characterized by an enhanced immune function associated with infection such as sepsis (Non-Patent Document 1).
Thus, a number of immunosuppressive agents are presently utilized as therapeutic agents for the above-mentioned disorders in clinical practice. However, as it now stands, there still remain many problems to be improved due to a failure to obtain a sufficient therapeutic effect and an unexpected occurrence of side effects.
A variety of cells such as T, B lymphocytes and factors are known to be involved in the inducement of the immune response. Since cyclosporin and tacrolimus, which are presently used for organ transplantation or the like, are restricted in their efficacy to T cells, there is a need for immunosuppressive agents which serve as agents for acting on more extensive immune mechanisms, with less side effects in clinical applications, and acting simultaneously on a variety of cells involved in the disorders.
Here, “a variety of cells involved in the disorders” are not limited to immune cells, i.e., T cells, B cells, monocytes, macrophages, NK cells, NKT cells, dendritic cells, neutrophils, basophils, eosinophils, mast cells or the like. They should include cells in which functions are affected by humoral factors released from immune cells or membrane receptors on the immune cells. Examples of these cells include, but are not limited to platelets, vascular endothelial cells, synoviocytes, osteoclasts, osteoblasts, chondrocytes, tracheal epithelial cells, or the like. In addition, in the case where the humoral factors are autoantibodies, cells expressing target antigens are also included.
Regarding benzimidazole ring-substituted s-triazine [1,3,5-triazine] derivatives and pyrimidine derivatives, the present inventors have studied their cytostatic activity on solid tumors, and have performed synthesis of a great number of such compounds as well as verification of the relationship between antitumor activity and chemical structure (see Patent Documents 1, 2, 3, 4 and 5).
In particular, s-triazine derivatives and pyrimidine derivatives having a specific substituent at position 2 of the benzimidazole ring were found to exhibit an enhanced cytostatic activity on solid tumors (see Patent Documents 3, 4 and 5). The processes for the production of such derivatives are described in these patent documents, but are not limited to these, and various reactions such as alkylation, alkylcarbonylation or the like may be induced in the final products to employ the resultant as final compounds.
Non-Patent Document 1: T. Munster et. al. Clin. Exp. Rheumatol., 17 (Suppl. 18): S29-S36 (1999);
Patent Document 1: WO 99/05138 pamphlet
Patent Document 2: WO 00/43385 pamphlet
Patent Document 3: WO 02/088112 pamphlet
Patent Document 4: WO 2004/037812 pamphlet
Patent Document 5: WO 2005/095389 pamphlet